SGK1-FoxO3-HIF通过调控肾小管细胞自噬参与肾缺血预适应保护机制

项目名称： SGK1-FoxO3-HIF通过调控肾小管细胞自噬参与肾缺血预适应保护机制

项目编号： No.81200494

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 张晓丽

作者单位： 复旦大学

项目金额： 24万元

中文摘要： 我们前期发现，预处理稳定肾小管细胞（PTEC）中低氧诱导因子1α（HIF-1α）表达可增强PTEC对肾缺血损伤的耐受（Mol Cell Biochem 2011）。目前认为，自噬是细胞适应缺血缺氧环境的一种自我保护机制。新近我们发现，缺血预适应（IPC）可激活PTEC自噬，同时伴有血清和糖皮质激素诱导的蛋白激酶1（SGK1）和HIF-1α蛋白表达上调，基因沉默SGK1可抑制HIF-1α表达，减弱PTEC自噬活性，大大削弱IPC的保护作用。本项目拟在体内、外建立PTEC的IPC模型，动态观察PTEC自噬情况及SGK1、FOXO3和HIF-1的定位、活性及表达规律，应用逐个阻断或激活的干预方法，明确SGK1-FOXO3-HIF在调控PTEC自噬中的作用及其相互间的作用关系。通过此研究，我们将从自噬角度进一步完善IPC肾保护作用的分子机制，为AKI的防治提供理论依据和新的思路。

中文关键词： 血清和糖皮质激素诱导的蛋白激酶1；肾小管细胞；自噬；缺血；

英文摘要： In our previous study, we found that pretreatment with prolyl hydroxylases inhibitor dimethyloxalylglycine could protect the kidney from ischemia reperfusion injure (IRI) mediated by activation of hypoxia-inducible factor (HIF-1α) and expression of heme oxygenase en (HO-1) in mice (Mol Cell Biochem 2011). Now autophagy is considered as a cell protection mechanism in response to ischemia/hypoxia injury. Serum- and glucocorticoid-inducible kinase 1 (SGK1) is possibly involved in the mediation of autophagy induced by ischemia for the homologous structure between SGK1 and protein kinase B (PKB) in the proximal epithelial tubular cell (PTEC). In our recent study, we found that ischemia precondition (IPC) could activate autophagy and up-regulate the expressions of SGK1 and HIF-1α. We also found that silence of SGK1 could inhibit the expression of HIF-1α, attenuate the autophagy level of PTEC and significantly weaken the protection of ischemia preconditioning. This study aims to observe antophagy and its role in PTEC using in vitro and in vivo models of IPC. We would also dynamically monitor the activation and expression of SGK1、forkhead box O3 (FOXO3) and HIF-1α and try to clarify their roles and interaction in mediation of antophagy in the precondition of PTEC. Through this study we try to make clear the molecular m

英文关键词： serum- and glucocorticoid-inducible kinase 1；tubular cell；autophagy；ischemia；